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1.
High-dose intravenous immunoglobulin versus albumin 4% in paediatric toxic shock syndrome: a randomised controlled feasibility study
Portefaix, A., Dhelens, C., Recher, M., Cour-Andlauer, F., Naudin, J., Mortamet, G., Joram, N., Tissières, P., Ginhoux, T., Kassai, B., et al
Archives of disease in childhood. 2024
Abstract
PURPOSE Toxic shock syndrome (TSS) is a rare disease responsible for significant morbidity and mortality. Intravenous immunoglobulin (IG) therapy in paediatric TSS could improve shock and organ failure, but more consistent efficacy and safety data are needed. Our objective was to determine whether a randomised clinical trial (RCT) assessing intravenous IG in TSS in children is feasible. METHODS We performed a multicentre, feasibility, double-blind RCT assessing efficacy of high-dose intravenous IG versus albumin 4% (control group) within the first 12 hours of shock onset. Included patients were aged above 1 month and below 18 years with suspected TSS and septic shock. Feasibility was assessed by measuring inclusion rate, protocol compliance and missing data regarding death and the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) Score. Other secondary clinical outcomes were evaluated during hospital stay, at 60 day and 1 year. RESULTS 28 patients, admitted in 6 paediatric intensive care units during 36 consecutive months and followed for 1 year, received the allocated treatment: 13 in intravenous IG group, 15 in control group. The median age was 10.6 years and the sex ratio was 1. Inclusion rate was above 50%, protocol deviations were below 30% and missing data regarding death and PELOD-2 Score below 10%. No difference concerning secondary clinical outcomes between groups was observed, and more adverse events were reported in the control group. CONCLUSION It seems to be feasible to conduct an RCT assessing intravenous IG efficacy and safety in paediatric TSS but must be realised internationally, with choice of a clinically relevant endpoint and a specific design in order to be realistic. TRIAL REGISTRATION NUMBER NCT02219165.
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2.
Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis
Wang, L., He, M., Wang, W., Li, S., Zhao, G.
European journal of pediatrics. 2024
Abstract
Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups. Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.
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3.
Cardiac assessment and inflammatory markers in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV2 (PIMS-TS) treated with methylprednisolone versus intravenous immunoglobulins: 6-month follow-up outcomes of the randomised controlled Swissped RECOVERY trial
Andre, M. C., Sanchez, C., Bressieux-Degueldre, S., Perez, M. H., Wütz, D., Blanchard-Rohner, G., Grazioli, S., Schöbi, N., Trück, J., Welzel, T., et al
EClinicalMedicine. 2024;67:102358
Abstract
BACKGROUND Previous findings from the Swissped RECOVERY trial showed that patients with Pediatric Inflammatory Multisystem Syndrome-Temporally Associated with SARS-CoV-2 (PIMS-TS) who were randomly assigned to intravenous immunoglobulins or methylprednisolone have a comparable length of hospital stay. Here, we report the 6-month follow-up outcomes of cardiac pathologies and normalisation of clinical or laboratory signs of inflammation from this study population. METHODS This pre-planned follow-up of patients with PIMS-TS included the Swissped RECOVERY Trial reports on the 6-month outcomes of the cohort after randomisation, with a focus on cardiac, haematological, and biochemical findings. The trial was an investigator-initiated randomised multicentre open-label two-arm trial in children and adolescents hospitalised with PIMS-TS at ten hospitals in Switzerland. Cardiological assessments and laboratory analyses were prospectively collected in the intention-to-treat analysis on pre-defined intervals after hospital discharge. Differences between randomised arms were investigated using Chi-square test for categorical and Wilcoxon test for continuous variables. The trial is registered with the Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS Between May 21, 2021 and April 15, 2022, 75 patients with a median age of 9.1 years (IQR 6.2-12.2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulin group). During follow-up, the incidence of abnormal left ventricular systolic function, coronary artery aneurysms (CAA), and other signs of inflammation were comparable in both groups. However, we detected cardiac abnormalities with low incidence and a mild degree grade of pathology. CAAs were observed in 2/38 children (5.3%) in the IVIG group and 1/37 children (2.7%) in the methylprednisolone group at 6-month follow-up (difference proportion 0.75; 95% confidence interval (CI) -0.05 to 1.0; p = 0.39). INTERPRETATION Methylprednisolone alone may be an acceptable first-line treatment as left ventricular systolic dysfunction and clinical/laboratory evidence for inflammation quickly resolved in all children. However, our findings need further confirmation through larger studies as our sample size is likely to be of insufficient power to address rare clinically relevant adverse outcomes. FUNDING NOMIS, Vontobel, and Gaydoul Foundation.
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4.
Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial
The Lancet. Child & adolescent health. 2024
Abstract
BACKGROUND Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment. METHODS We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients <30 kg; 8mg/kg in patients ≥30 kg, up to a maximum dose of 800 mg), or subcutaneous anakinra (2 mg/kg once per day in patients ≥10 kg). Randomisation was by use of a web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was duration of hospital stay. Analysis was by intention to treat. For treatments assessed in each randomisation, a single Bayesian framework assuming uninformative priors for treatment was used to jointly assess the efficacy of each intervention compared with usual care. The trial was registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS Between May 18, 2020, and Jan 20, 2022, 237 children with PIMS-TS were enrolled and included in the intention-to-treat analysis. Of the 214 patients who entered the first randomisation, 73 were assigned to receive intravenous immunoglobulin, 61 methylprednisolone, and 80 usual care. Of the 70 children who entered the second randomisation (including 23 who did not enter the first randomisation), 28 were assigned to receive tocilizumab, 14 anakinra, and 28 usual care. Mean age was 9·5 years (SD 3·8) in the randomisation and 9·6 years (3·6) in the second randomisation. 118 (55%) of 214 patients in the first randomisation and 39 (56%) of 70 patients in the second randomisation were male. 130 (55%) of 237 patients were Black, Asian, or minority ethnic, and 105 (44%) were White. Mean duration of hospital stay was 7·4 days (SD 0·4) in children assigned to intravenous immunoglobulin and 7·6 days (0·4) in children assigned to usual care (difference -0·1 days, 95% credible interval [CrI] -1·3 to 1·0; posterior probability 59%). Mean duration of hospital stay was 6·9 days (SD 0·5) in children assigned to methylprednisolone (difference from usual care -0·7 days, 95% CrI -1·9 to 0·6; posterior probability 87%). Mean duration of hospital stay was 6·6 days (SD 0·7) in children assigned to second-line tocilizumab and 9·9 days (0·9) in children assigned to usual care (difference -3·3 days, 95% CrI -5·6 to -1·0; posterior probability >99%). Mean duration of hospital stay was 8·5 days (SD 1·2) in children assigned to anakinra (difference from usual care -1·4 days, 95% CrI -4·3 to 1·8; posterior probability 84%). Two persistent coronary artery aneurysms were reported among patients assigned to usual care in the first randomisation. There were few cardiac arrythmias, bleeding, or thrombotic events in any group. Two children died; neither was considered related to study treatment. INTERPRETATION Moderate evidence suggests that, compared with usual care, first-line intravenous methylprednisolone reduces duration of hospital stay for children with PIMS-TS. Good evidence suggests that second-line tocilizumab reduces duration of hospital stay for children with inflammation refractory to initial treatment. Neither intravenous immunoglobulin nor anakinra had any effect on duration of hospital stay compared with usual care. FUNDING Medical Research Council and National Institute of Health Research.
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5.
Intravenous immunoglobulin in the management of neonatal sepsis: A randomised controlled trial
Rizvi MQ, Singh MV, Mishra N, Shrivastava A, Maurya M, Siddiqui SA
Tropical doctor. 2023;:494755221138689
Abstract
Sepsis is a leading cause of neonatal mortality and morbidity in low and middle-income countries. We designed a double-blinded randomised controlled trial in a neonatal intensive care unit (NICU) of a tertiary care teaching hospital to determine the role of intravenous immunoglobulin (IVIG) in decreasing hospital stay. Eighty neonates with clinical features of sepsis were enrolled in the study and placebo groups to receive 500 mg/kg of IVIG for three consecutive days or a placebo. The primary outcome measure was duration of hospital stay in days. The babies in both groups were comparable in terms of birth weight, gestation and sex distribution. There was no significant difference in duration of hospital stay (days) in the study and placebo groups. We found that treatment with IVIG did not shorten the duration of hospital stay in our setting.
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6.
Safety and efficacy of pharmacological approaches available for multisystem inflammatory syndrome in children (MIS-C): a systematic review
Velusamy, Y., Vivekanandan, G., Romli, M. H., Shankar, A., Karuppiah, T., Yubbu, P.
The Turkish journal of pediatrics. 2023;65(5):719-738
Abstract
BACKGROUND To describe the existing pharmacological managements for Multisystem Inflammatory Syndrome in Children (MIS-C) in a systematic way, to identify the available pharmacological managements in MIS-C, evaluate its safety and efficacy and identify the best treatment procedures for practice recommendation. METHODS A systematic search using six databases was conducted on August 18, 2021, updated in January 26th 2023. Terminologies that were used in this search are children, MIS-C/PIMS and SARS-CoV-2. A PRISMA flow diagram was used to report the study selection process. Quality analysis was done based on NOS and GRADE tools. Data synthesis was conducted by extracting the information on drugs used, efficacy and side effects. RESULTS From the 32 articles included, a total of 2331 children with MIS-C were studied. The main pharmacological approaches were immunomodulatory therapy, i.e., intravenous immunoglobulin (IVIG) (77.3%), steroids (60.5%), and a combination of IVIG and steroids (41.3%). IVIG and steroids were found to be potentially effective and safe treatments for MIS-C. Combination of IVIG and steroids was found favorable in severe cases with higher recovery rate. Refractory treatments include second dose of initial treatment and biological response modifier drugs like anakinra, tocilizumab, infliximab. A small number of studies investigating supportive treatment consisted of vasoactive, inotropic and anticoagulation. The mortality rate was 1.28% and only three studies reported side effects from the treatment. Evidence of outcome from GRADE were mostly at moderate, low and very low levels. CONCLUSIONS This review provides preliminary evidence to support the current standard treatment practices in managing MIS-C pharmacologically. However, comprehensive investigation is required using clinical trials to provide stronger outcome evidence.
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7.
Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial
Welzel T, Atkinson A, Schöbi N, Andre MC, Bailey DGN, Blanchard-Rohner G, Buettcher M, Grazioli S, Koehler H, Perez MH, et al
The Lancet. Child & adolescent health. 2023
Abstract
BACKGROUND The emergence of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) led to the widespread use of anti-inflammatory treatments in the absence of evidence from randomised controlled trials (RCTs). We aimed to assess the effectiveness of intravenous methylprednisolone compared with intravenous immunoglobulins. METHODS This is an open-label, multicentre, two-arm RCT done at ten hospitals in Switzerland in children younger than 18 years hospitalised with PIMS-TS (defined as age <18 years; fever and biochemical evidence of inflammation, and single or multiorgan dysfunction; microbiologically proven or putative contact with SARS-CoV-2; and exclusion of any other probable disease). Patients were randomly assigned 1:1 to intravenous methylprednisolone (10 mg/kg per day for 3 days) or intravenous immunoglobulins (2 g/kg as a single dose). The primary outcome was length of hospital stay censored at day 28, death, or discharge. Secondary outcomes included proportion and duration of organ support. Analyses were done by intention-to-treat. The study was registered with Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS Between May 21, 2021, and April 15, 2022, 75 patients with a median age of 9·1 years (IQR 6·2-12·2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulins group). The median length of hospital stay was 6·0 days (IQR 4·0-8·0) in the methylprednisolone group and 6·0 days (IQR 5·0-8·8) in the intravenous immunoglobulins group (estimated effect size -0·037 of the log(10) transformed times, 95% CI -0·13 to 0·065, p=0·42). Fewer patients in the methylprednisolone group (ten [27%] of 37) required respiratory support compared with the intravenous immunoglobulin group (21 [55%] of 38, p=0·025). Need and duration of inotropes, admission to intensive care units, cardiac events after baseline, and major bleeding and thrombotic events were not significantly different between the study groups. INTERPRETATION In this RCT, treatment with methylprednisolone in children with PIMS-TS did not significantly affect the length of hospital stay compared with intravenous immunoglobulins. Intravenous methylprednisolone could be an acceptable first-line treatment in children with PIMS-TS. FUNDING NOMIS Foundation, Vontobel Foundation, and Gaydoul Foundation.
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8.
Gamma globulin combined with acyclovir for children with infectious mononucleosis and their effect on immune function
Li, Y., Chen, B.
American journal of translational research. 2023;15(6):4399-4407
Abstract
BACKGROUND Infectious mononucleosis (IM) is characterized by pharyngitis, cervical lymphadenopathy, fatigue and fever. IM is most commonly seen in primary Epstein-Barr virus (EBV) infection, with higher occurrence in children. OBJECTIVE To explore the value of gamma globulin combined with acyclovir for IM children and their impact on immune function. METHODS This prospective randomized controlled study recruited 111 children under 14 years old with IM from Anhui Provincial Children's Hospital during March 2019 and March 2022. Among them, 11 children dropped out, and 100 eligible children were randomized 1:1 into a control group and a study group. The control group received acyclovir, and the study group received additional gamma globulin. The baseline data, clinical efficacy, immune function, and adverse reactions were collected and compared. RESULTS The study group had a shorter antipyretic time, lymph node reduction time, pharyngitis improvement time, and hospital stay compared to the control group (P < 0.05). The study group yielded lower levels of total white blood cell count, alanine aminotransferase, and creatine kinase-MB than the control group (P < 0.05). After treatment, the levels of CD3+ and CD8+ were lower, and the levels of CD4+, CD4+/CD8+, IgA, and IgG were higher in the study group than those in the control group (all P < 0.05). The incidence of adverse reactions between the two groups was comparable (14.00% vs. 24.00%). The positive rates of EBV-specific antibody and nuclear antigen in the study group were lower than those in the control group (P < 0.05). CONCLUSION The combined treatment of gamma globulin and acyclovir is a promising alternative for patients with IM compared to acyclovir alone. This combined regimen shortens the duration of clinical manifestations in children, promotes the recovery of laboratory indices, improves clinical efficacy, and enhances immune function. Furthermore, its safety profile is acceptable, warranting its further promotion.
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9.
Immunomodulatory Therapy for MIS-C
Ouldali, N., Son, M. B. F., McArdle, A. J., Vito, O., Vaugon, E., Belot, A., Leblanc, C., Murray, N. L., Patel, M. M., Levin, M., et al
Pediatrics. 2023;152(1)
Abstract
CONTEXT Studies comparing initial therapy for multisystem inflammatory syndrome in children (MIS-C) provided conflicting results. OBJECTIVE To compare outcomes in MIS-C patients treated with intravenous immunoglobulin (IVIG), glucocorticoids, or the combination thereof. DATA SOURCES Medline, Embase, CENTRAL and WOS, from January 2020 to February 2022. STUDY SELECTION Randomized or observational comparative studies including MIS-C patients <21 years. DATA EXTRACTION Two reviewers independently selected studies and obtained individual participant data. The main outcome was cardiovascular dysfunction (CD), defined as left ventricular ejection fraction < 55% or vasopressor requirement ≥ day 2 of initial therapy, analyzed with a propensity score-matched analysis. RESULTS Of 2635 studies identified, 3 nonrandomized cohorts were included. The meta-analysis included 958 children. IVIG plus glucocorticoids group as compared with IVIG alone had improved CD (odds ratio [OR] 0.62 [0.42-0.91]). Glucocorticoids alone group as compared with IVIG alone did not have improved CD (OR 0.57 [0.31-1.05]). Glucocorticoids alone group as compared with IVIG plus glucocorticoids did not have improved CD (OR 0.67 [0.24-1.86]). Secondary analyses found better outcomes associated with IVIG plus glucocorticoids compared with glucocorticoids alone (fever ≥ day 2, need for secondary therapies) and better outcomes associated with glucocorticoids alone compared with IVIG alone (left ventricular ejection fraction < 55% ≥ day 2). LIMITATIONS Nonrandomized nature of included studies. CONCLUSIONS In a meta-analysis of MIS-C patients, IVIG plus glucocorticoids was associated with improved CD compared with IVIG alone. Glucocorticoids alone was not associated with improved CD compared with IVIG alone or IVIG plus glucocorticoids.
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10.
Clinical efficacy of IgM-enriched immunoglobulin as adjunctive therapy in neonatal and pediatric sepsis: a systematic review and meta-analysis
Dinleyici, E. C., Frey, G., Kola, E., Wippermann, U., Bauhofer, A., Staus, A., Griffiths, P., Azharry, M., Rohsiswatmo, R.
Frontiers in pediatrics. 2023;11:1239014
Abstract
BACKGROUND Sepsis is a major cause of mortality and morbidity globally, with around one-quarter of all sepsis-related deaths occurring in children under the age of 5. We conducted a meta-analysis and systematic review of the literature to evaluate the clinical effectiveness of an IgM-enriched immunoglobulin preparation in pediatrics patients and neonates with sepsis. METHODS Systematic searches of PubMed, the Cochrane Library and Embase databases were performed in November 2022, with no date limitations, to identify studies in which IgM-enriched immunoglobulin was used as adjunctive therapy in neonatal and pediatric patients with sepsis. RESULTS In total, 15 studies fulfilled the eligibility criteria, 13 neonatal studies and 2 pediatric studies. Pooled estimates from all studies indicated that mortality rates were significantly lower in patients who received treatment with the IgM-enriched immunoglobulin compared with controls (OR 0.41; 95% CI 0.32-0.55). Further analyses in neonatal studies, alone, showed a significant benefit with longer treatment durations (>3 days) vs. the recommended treatment duration (3 days) (OR 0.32; 95% CI 0.22-0.47) vs. (OR 0.61; 95% CI 0.41-0.92). Treatment with IgM-enriched immunoglobulin was associated with a lower mortality risk compared with controls in prospective studies vs. retrospective analyses (OR 0.37; 95% CI 0.27-0.51) vs. (OR 0.73; 95% CI 0.41-1.30). CONCLUSIONS This systematic review suggests that adjunctive treatment with IgM-enriched immunoglobulin may reduce the risk of mortality in neonatal and pediatric populations. However, large randomized controlled trials are required to further substantiate and evaluate these findings.